Revertant fibres and dystrophin traces in Duchenne muscular dystrophy: Implication for clinical trials

Duchenne muscular dystrophy (DMD) is characterised by the absence of dystrophin in muscle biopsies, although residual dystrophin can be present, either as dystrophin-positive (revertant) fibres or traces. As restoration of dystrophin expression is the end point of clinical trials, such residual dystrophin is a key factor in recruitment of patients and may also confound the analysis of dystrophin restoration in treated patients, if, as previously observed in the mdx mouse, revertant fibres increase with age. In 62% of the diagnostic biopsies reports of 65 DMD patients studied, traces or revertants were recorded with no correlation between traces or revertants, the patients' performance, or corticosteroids response. In nine of these patients, there was no increase in traces or revertants in biopsies taken a mean of 8.23 years (5.8-10.4 years) after the original diagnostic biopsy. This information should help in the design and execution of clinical trials focused on dystrophin restoration strategies. (C) 2010 Elsevier B.V. All rights reserved

Cognitive architectures as Lakatosian research programmes: two case studies

Cognitive architectures - task-general theories of the structure and function of the complete cognitive system - are sometimes argued to be more akin to frameworks or belief systems than scientific theories. The argument stems from the apparent non-falsifiability of existing cognitive architectures. Newell was aware of this criticism and argued that architectures should be viewed not as theories subject to Popperian falsification, but rather as Lakatosian research programs based on cumulative growth. Newell's argument is undermined because he failed to demonstrate that the development of Soar, his own candidate architecture, adhered to Lakatosian principles. This paper presents detailed case studies of the development of two cognitive architectures, Soar and ACT-R, from a Lakatosian perspective. It is demonstrated that both are broadly Lakatosian, but that in both cases there have been theoretical progressions that, according to Lakatosian criteria, are pseudo-scientific. Thus, Newell's defense of Soar as a scientific rather than pseudo-scientific theory is not supported in practice. The ACT series of architectures has fewer pseudo-scientific progressions than Soar, but it too is vulnerable to accusations of pseudo-science. From this analysis, it is argued that successive versions of theories of the human cognitive architecture must explicitly address five questions to maintain scientific credibility

Prodigious submarine landslides during the inception and early growth of volcanic islands

Volcanic island inception applies large stresses as the ocean crust domes in response to magma ascension and is loaded by eruption of lavas. There is currently limited information on when volcanic islands are initiated on the seafloor, and no information regarding the seafloor instabilities island inception may cause. The deep sea Madeira Abyssal Plain contains a 43 million year history of turbidites among which many originate from mass movements in the Canary Islands. Here, we investigate the composition and timing of a distinctive group of turbidites that we suggest represent a new unique record of large-volume submarine landslides triggered during the inception, submarine shield growth, and final subaerial emergence of the Canary Islands. These slides are predominantly multi-stage and yet represent among the largest mass movements on the Earth’s surface up to three or more-times larger than subaerial Canary Islands flank collapses. Thus whilst these deposits provide invaluable information on ocean island geodynamics they also represent a significant, and as yet unaccounted, marine geohazard

Comparison of Self-Reported Alcohol Consumption to Phosphatidylethanol Measurement among HIV-Infected Patients Initiating Antiretroviral Treatment in Southwestern Uganda

Background: Alcohol consumption among HIV-infected patients may accelerate HIV disease progression or reduce antiretroviral therapy adherence. Self-reported alcohol use is frequently under-reported due to social desirability and recall bias. The aim of this study was to compare self-reported alcohol consumption to phosphatidylethanol (PEth), a biomarker of alcohol consumption, and to estimate the correlation between multiple measures of self-reported alcohol consumption with PEth. Methods: The Uganda AIDS Rural Treatment Outcomes (UARTO) cohort is located in southwestern Uganda and follows patients on ART to measure treatment outcomes. Patients complete standardized questionnaires quarterly including questions on demographics, health status and alcohol consumption. Baseline dried blood spots (DBS) were collected and retrieved to measure PEth. Results: One hundred fifty samples were tested, and 56 (37.3%) were PEth positive (≥8 ng/mL). Of those, 51.7% did not report alcohol use in the past month. Men were more likely to under-report compared to women, OR 2.9, 95% CI = 1.26, 6.65) and those in the higher economic asset categories were less likely to under-report compared to those in the lowest category (OR = 0.41 95% CI: 0.17, 0.94). Among self-reported drinkers (n = 31), PEth was highly correlated with the total number of drinking days in the last 30 (Spearman R = 0.73, p<0.001). Conclusions: Approximately half of HIV infected patients initiating ART and consuming alcohol under-report their use of alcohol. Given the high prevalence, clinicians should assess all patients for alcohol use with more attention to males and those in lower economic asset categories who deny alcohol use. Among those reporting current drinking, self-reported drinking days is a useful quantitative measure

Boundaries of Semantic Distraction: Dominance and Lexicality Act at Retrieval

Three experiments investigated memory for semantic information with the goal of determining boundary conditions for the manifestation of semantic auditory distraction. Irrelevant speech disrupted the free recall of semantic category-exemplars to an equal degree regardless of whether the speech coincided with presentation or test phases of the task (Experiment 1) and occurred regardless of whether it comprised random words or coherent sentences (Experiment 2). The effects of background speech were greater when the irrelevant speech was semantically related to the to-be-remembered material, but only when the irrelevant words were high in output dominance (Experiment 3). The implications of these findings in relation to the processing of task material and the processing of background speech is discussed

Novel Approaches to Inhibition of Gastric Acid Secretion

The gastric H,K-adenosine triphosphatase (ATPase) is the primary target for treatment of acid-related diseases. Proton pump inhibitors (PPIs) are weak bases composed of two moieties, a substituted pyridine with a primary pKa of about 4.0 that allows selective accumulation in the secretory canaliculus of the parietal cell, and a benzimidazole with a second pKa of about 1.0. Protonation of this benzimidazole activates these prodrugs, converting them to sulfenic acids and/or sulfenamides that react covalently with one or more cysteines accessible from the luminal surface of the ATPase. The maximal pharmacodynamic effect of PPIs as a group relies on cyclic adenosine monophosphate–driven H,K-ATPase translocation from the cytoplasm to the canalicular membrane of the parietal cell. At present, this effect can only be achieved with protein meal stimulation. Because of covalent binding, inhibitory effects last much longer than their plasma half-life. However, the short dwell-time of the drug in the blood and the requirement for acid activation impair their efficacy in acid suppression, particularly at night. All PPIs give excellent healing of peptic ulcer and produce good, but less than satisfactory, results in reflux esophagitis. PPIs combined with antibiotics eradicate Helicobacter pylori, but success has fallen to less than 80%. Longer dwell-time PPIs promise to improve acid suppression and hence clinical outcome. Potassium-competitive acid blockers (P-CABs) are another class of ATPase inhibitors, and at least one is in development. The P-CAB under development has a long duration of action even though its binding is not covalent. PPIs with a longer dwell time or P-CABs with long duration promise to address unmet clinical needs arising from an inability to inhibit nighttime acid secretion, with continued symptoms, delayed healing, and growth suppression of H. pylori reducing susceptibility to clarithromycin and amoxicillin. Thus, novel and more effective suppression of acid secretion would benefit those who suffer from acid-related morbidity, continuing esophageal damage and pain, nonsteroidal anti-inflammatory drug–induced ulcers, and nonresponders to H. pylori eradication

A model for quality of life measures in patients with dementia: Lawron's next step

The introduction of drugs that are claimed to improve cognitive function and activities of daily living in patients with Alzheimer's disease raises the question of whether these drugs also influence dementia patients' quality of life (QOL). We describe a hierarchic model of QOL of dementia patients, which can guide the development of measurement instruments. After initially discussing broadly QOL research, we focus on two highly important characteristics of the concept, its broadness and subjectivity, against the background of the relevant literature on QOL in dementia. Dementia-specific dimensions and domains are presented. We identify psychological well-being as the core dimension for QOL of patients with dementia. Copyright © 2004 S. Karger AG, Basel

Infrared cameras overestimate skin temperature during rewarming from cold exposure

This is an accepted manuscript of an article published by Elsevier in Journal of Thermal Biology on 03/05/2020, available online: https://doi.org/10.1016/j.jtherbio.2020.102614 The accepted version of the publication may differ from the final published version.Objective The primary aim of this study was to assess the accuracy of an infrared camera and that of a skin thermistor, both commercially available. The study aimed to assess the agreement over a wide range of skin temperatures following cold exposure. Methods Fifty-two males placed their right hand in a thin plastic bag and immersed it in 8 °C water for 30 min whilst seated in an air temperature of 30 °C. Following hand immersion, participants removed the bag and rested their hand at heart level for 10 min. Index finger skin temperature (Tsk) was measured with a thermistor, affixed to the finger pad, and an infrared camera measured 1 cm distally to the thermistor. Agreement between the infrared camera and thermistor was assessed by mean difference (infrared camera minus thermistor) and 95% limits of agreement analysis, accounting for the repeated measures over time. The clinically significant threshold for Tsk differences was set at ±0.5 °C and limits of agreement ±1 °C. Results As an average across all time points, the infrared camera recorded Tsk 1.80 (SD 1.16) °C warmer than the thermistor, with 95% limits of agreement ranging from −0.46 °C to 4.07 °C. Conclusion Collectively, the results show the infrared camera overestimated Tsk at every time point following local cooling. Further, measurement of finger Tsk from the infrared camera consistently fell outside the acceptable level of agreement (i.e. mean difference exceeding ±0.5 °C). Considering these results, infrared cameras may overestimate peripheral Tsk following cold exposure and clinicians and practitioners should, therefore, adjust their risk/withdrawal criteria accordingly.Published versio